Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK/ERK pathways

[en] In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar(9), Met(O-2)(11)]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2-bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Go6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4beta-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.

Research center :

Giga-Neurosciences - ULiège

Disciplines :

Neurosciences & behavior
Biochemistry, biophysics & molecular biology

Author, co-author :

Lallemend, François

Lefèbvre, Philippe ; Université de Liège - ULiège > Département des sciences cliniques > Oto-rhino-laryngologie et audiophonologie

Hans, Grégory ; Université de Liège - ULiège > Anesthésie et réanimation

Rigo, Jean-michel

Van De Water, T. R.

Moonen, Gustave ; Université de Liège - ULiège > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine

Malgrange, Brigitte ; Université de Liège - ULiège > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc.

Language :

English

Title :

Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK/ERK pathways

Publication date :

October 2003

Journal title :

Journal of Neurochemistry

ISSN :

0022-3042

eISSN :

1471-4159

Publisher :

Blackwell Publishing Ltd, Oxford, United Kingdom

Volume :

Issue :

Pages :

508-521

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]

Available on ORBi :

since 25 November 2009

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